TW201504215A - Method for producing pyridazine compound - Google Patents

Abstract

A pyridazine compound represented by formula [1]: which is useful as an active ingredient of a plant disease control agent can be produced, by steps of obtaining a compound represented by formula [3]: by reacting a compound represented by formula [4]: with a compound represented by formula [5]: obtaining a compound represented by formula [2]: by deprotecting the compound [3]; and reacting the compound [2] with a chlorinating agent.

Description

嗒 How to make a compound

The present invention relates to 嗒 Method for producing compound, intermediate product thereof, and method for producing the intermediate product

In U.S. Patent No. 7,569,518, the compound represented by the formula [1] is described: In the formula, X represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and Y represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and the compound has an active ingredient for use as a plant disease controlling agent, and an advantageous production thereof method.

Furthermore, U.S. Patent No. 2009/156608 discloses certain types of defects. Compound.

The present invention provides a crucible represented by the formula [1] A method for producing a compound, an intermediate product thereof, and a method for producing the intermediate product.

The invention is more specifically described as follows:

«1» A method for producing a compound [1], comprising the steps of: reacting a compound represented by the formula [4] with a compound represented by the formula [5] to obtain a compound represented by the formula [3]: Wherein Q represents a protecting group which is a C1 to C12 alkylsulfonyl group which is optionally halogenated, a C6 to C24 arylsulfonyl group which is optionally substituted with at least one atom or group selected from Group A, or At least one hydrogen atom on the benzene ring is optionally substituted with a benzyl group selected from an atom or group of the group B; X represents a hydrogen atom, a halogen atom or a methyl group, and Y represents a hydrogen atom, a halogen atom or a methyl group. (hereinafter referred to as compound [3]); Group A: a group of C1 to C4 alkoxy groups, a halogen atom and a nitro group which are halogenated as needed, Group B: C1 to C4 alkyl groups which are halogenated as needed, A halogenated C1 to C4 alkoxy group, a halogen atom and a nitro group are required; Wherein R ¹ represents a C1 to C12 alkyl group which is optionally halogenated, or a C6 to C24 aryl group which is optionally substituted with at least one atom or group selected from Group A, and Q and Y have the same meanings as described above. (hereinafter referred to as compound [4]); Wherein X is the same as defined above, and Z represents a chlorine atom or a bromine atom (hereinafter referred to as compound [5]); and a compound represented by the formula [2] is obtained by deprotection of the compound [3]: In the formula, X and Y have the same meanings as described above (hereinafter referred to as the compound [2]); and the compound [2] is reacted with a chlorinating agent to obtain a compound represented by the formula [1]: In the formula, X and Y have the same meanings as described above. (hereinafter referred to as compound [1])

«2» A method for producing the compound [1], comprising the steps of: reacting the compound [4] with the compound [5] to obtain the compound [3]; and mixing the compound [3] with phosphorus oxychloride and heating the mixture And the compound [1].

«3» A method for producing a compound [1], comprising the step of reacting a compound represented by the formula [4A] with a compound [5] to obtain a compound represented by the formula [3A]: Wherein X and Y have the same meanings as defined above, and Q ¹ represents a C1 to C12 alkylsulfonyl group which is optionally halogenated, or a C6 which is optionally substituted with at least one atom or group selected from Group A. To C24 arylsulfonyl group, group A: a group of halogenated C1 to C4 alkoxy groups, a halogen atom and a nitro group as required (hereinafter referred to as compound [3A]) Wherein R ¹ , Y and Q ¹ have the same meanings as described above (hereinafter referred to as compound [4A]): and a compound [3A] is mixed with a secondary amine and then a chlorinating agent is added to the mixture to obtain a compound [ 1].

«4» compound [3].

«5» A method for producing a compound [3] obtained by reacting a compound [4] with a compound [5].

«6» compound [4].

Fig. 1 is a PXRD pattern of the type 1 obtained in Reference Example 11.

Fig. 2 is a DSC/TGA trajectory of the type 1 obtained in Reference Example 11.

Fig. 3 is a PXRO pattern of the type 2 obtained in Reference Example 12.

Fig. 4 is a DSC/TGA trajectory of the type 2 obtained in Reference Example 12.

Fig. 5 is a PXRO pattern of the type 3 obtained in Reference Example 13.

Fig. 6 is an OSC/TGA trajectory of the type 3 obtained in Reference Example 13.

Figure 7 is an overlay of the PXRD patterns of Type 1 to Type 3.

Hereinafter, the present invention will be described in detail.

The halogen atom herein means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among these, a chlorine atom and a fluorine atom are preferable.

The halogenated C1 to C12 alkyl group as used herein denotes a group in which at least one hydrogen atom of the C1 to C12 alkyl group is optionally substituted by a halogen atom, and when two or more halogen atoms are substituted, The halogen atoms may be different from each other. Examples of the C1 to C12 alkyl group which may be halogenated as needed include methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group, pentyl group, neopentyl group, 1-ethylpropyl group, hexyl group, Heptyl, octyl, decyl, decyl, undecyl, dodecyl, isopentyl, secondary isopentyl (1,2-dimethylpropyl), tertiary hexyl (2,3-di Methyl-2-butyl), cyclopropyl, cyclohexyl, 2,2,2-trichloroethyl, trifluoromethyl, pentafluoroethyl, 12-chlorododecyl, 3,3-dichloro-3-fluoropropyl, and dichlorofluoromethyl.

Among these, a halogenated C1 to C4 alkyl group is desirable as needed.

The C1 to C12 alkyl group herein represents a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. , tertiary butyl, pentyl, neopentyl, 1-ethylpropyl, hexyl, heptyl, octyl, decyl, decyl, undecyl, dodecyl, isopentyl, secondary isoprene (1,2-dimethylpropyl), tertiary hexyl, cyclopropyl, cyclohexyl, cyclohexylmethyl, norbornyl and adamantyl. Among these, a C1 to C4 alkyl group is desirable.

The halogenated C1 to C4 alkyl group as used herein denotes a group wherein at least one hydrogen atom of the C1 to C4 alkyl group is optionally substituted by a halogen atom, and when two or more halogen atoms are substituted, The halogen atoms can be different from each other. Examples of the C1 to C4 alkyl group which may be halogenated as needed include methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, tert-butyl group, 2,2,2-trichloroethyl group, and three groups. Fluoromethyl, pentafluoroethyl, 3,3-dichloro-3-fluoropropyl, dichlorofluoromethyl.

The C1 to C4 alkyl group herein represents a linear, branched or cyclic alkyl group having 1 to 4 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cyclopropyl group. Base, butyl and tertiary butyl.

The C6 to C24 aryl group as used herein, optionally substituted with at least one atom or group selected from Group A, represents a group wherein at least one hydrogen atom of the C6 to C24 aryl group is optionally selected from Group A atoms or groups. Take Generation, and when two or more atoms or groups are substituted, the atoms or groups may be different from each other. Examples of the C6 to C24 aryl group which may be optionally substituted include phenyl, tolyl, nitrophenyl, chlorophenyl, anisyl, chlorofluorophenyl, dimethoxyphenyl, pentafluorophenyl, trifluorobenzene. Base, trifluoromethylphenyl, trifluoromethoxyphenyl and chlorotriphenyl. Among these, a substituted C6 to C14 aryl group is desirable as desired, and a phenyl group which is optionally substituted, as desired, is preferred.

The aryl group herein means a substituent which removes one hydrogen atom from the aromatic ring of the aromatic hydrocarbon, and the carbon number means an alkyl group which is directly bonded to the aromatic ring.

The C6 to C24 aryl group herein means a monocyclic or polycyclic aryl group having 6 to 24 carbon atoms, and these rings may be condensed. Examples of the C6 to C24 aryl group include a phenyl group, a tolyl group, a mesityl group, a naphthyl group, a biphenyl group, a fluorenyl group, a decyl group, a triphenyl group, a binaphthyl group, and a phenyl group. Terphenyl group, tetraphenylene, 3',5'-diphenylbiphenyl, indanyl group, and di-tertiary butylphenyl. Among these, the C6 to C14 aryl group is ideal.

The C6 to C14 aryl group in which at least one hydrogen atom is optionally substituted with an atom or a group selected from the group A represents a group wherein at least one hydrogen atom of the C6 to C14 aryl group is optionally selected from the group A. Substituted by an atom or group, when two or more atoms or groups are substituted, the atoms or groups may be different from each other. Examples of the C6 to C14 aryl group which may be optionally substituted include a phenyl group, a tolyl group, a chlorophenyl group, an anisyl group, and a chlorofluorophenyl group.

The C6 to C14 aryl group herein means 6 to 14 carbons A monocyclic or polycyclic aryl group of atoms, and such rings may be condensed. Examples of the C6 to C14 aryl group include a phenyl group, a tolyl group, a naphthyl group, a biphenyl group, an indanyl group, and a di-tertiary butylphenyl group. Among these, a phenyl group and a 4-tolyl group are preferred.

The halogenated C1 to C12 alkylsulfonyl group as used herein denotes a group in which at least one hydrogen atom of the C1 to C12 alkylsulfonyl group is optionally substituted by a halogen atom, and when there are two or more When a plurality of halogen atoms are substituted, the halogen atoms may be different from each other. Examples of the C1 to C12 alkylsulfonyl group which may be halogenated as needed include methylsulfonyl, cyclohexylsulfonyl, trifluoromethylsulfonyl, 2,2,2-trichloroethylsulfonyl, Pentafluoroethylsulfonyl, 3,3-dichloro-3-fluoropropylsulfonyl, 12-chlorododecylsulfonyl. Among these, a halogenated C1 to C4 alkylsulfonyl group is desirable as needed.

The C1 to C12 alkylsulfonyl group herein means a linear, branched or cyclic alkylsulfonyl group having 1 to 12 carbon atoms, and examples thereof include a methylsulfonyl group and an ethyl group. Sulfonyl, propylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, fluorenylsulfonyl, fluorenyl Sulfonyl, eleven sulfonyl, dodecylsulfonyl, isopentylsulfonyl, second isopentylsulfonyl, tertiary hexylsulfonyl, cyclopropylsulfonyl, cyclohexyl Sulfonyl, cyclohexylmethylsulfonyl, norbornylsulfonyl and adamantylsulfonyl. Among these, a C1 to C4 alkylsulfonyl group is preferred.

The halogenated C1 to C4 alkylsulfonyl group as used herein denotes a group wherein at least one hydrogen atom of the C1 to C4 alkylsulfonyl group is optionally substituted by a halogen atom, and when there are two or more Halogen atom In the meantime, the halogen atoms may be different from each other. Examples of the C1 to C4 alkylsulfonyl group which may be halogenated as needed include methylsulfonyl, ethylsulfonyl, cyclopropylsulfonyl, trifluoromethylsulfonyl, 2, 2, 2-tri Chloroethylsulfonyl, and pentafluoroethylsulfonyl. Among these, a methylsulfonyl group, an ethylsulfonyl group, and a trifluoromethylsulfonyl group are preferable.

The C1 to C4 alkylsulfonyl group herein means a linear, branched or cyclic alkylsulfonyl group having 1 to 4 carbon atoms, and examples thereof include a methylsulfonyl group and an ethyl group. Sulfosyl, propylsulfonyl, cyclopropylsulfonyl and tert-butylsulfonyl.

The C6 to C24 arylsulfonyl group, optionally substituted by at least one atom or group selected from Group A, represents a C6 to C24 arylsulfonyl group, wherein the C6 to C24 arylsulfonyl group is at least A hydrogen atom may be optionally substituted with an atom or group selected from Group A. When two or more substituted atoms or groups are present, the atoms or groups may be different from each other. Examples of the C6 to C24 arylsulfonyl group which may be optionally substituted include a phenylsulfonyl group, a tolylsulfonyl group, a naphthylsulfonyl group, a 2,4,6-trimethylol group (mesityl group). , biphenylsulfonyl, fluorenylsulfonyl, fluorenylsulfonyl, triphenylsulfonyl, binaphthylsulfonyl, tetraphenylsulfonyl, 3', 5'-di Phenylbiphenylsulfonyl, nitrophenylsulfonyl, chlorophenylsulfonyl, anisylsulfonyl, chlorofluorophenylsulfonyl, dimethoxyphenylsulfonyl, pentafluorobenzene Sulfosyl, trifluoromethylphenylsulfonyl, trifluoromethoxyphenylsulfonyl and chlorotriphenylsulfonyl. Among these, a substituted C6 to C14 arylsulfonyl group is desirable as desired, and particularly a substituted phenylsulfonyl group is desirable.

The C6 to C24 arylsulfonyl group herein means a monocyclic or polycyclic arylsulfonyl group having 6 to 24 carbon atoms, and the rings may be condensed. Examples of the C6 to C24 arylsulfonyl group include a phenylsulfonyl group, a tolylsulfonyl group, a naphthylsulfonyl group, a biphenylsulfonyl group, a sulfonyl group, a mercaptosulfonyl group, a terphenyl group. Sulfosyl, dinaphthylsulfonyl, tetraphenylsulfonyl, 3',5'-diphenylbiphenylsulfonyl, indanyl group, sulfonyl and di- Tert-butyl phenyl sulfonyl. Among these, a C6 to C14 arylsulfonyl group is preferred.

The C6 to C14 arylsulfonyl group as used herein, optionally substituted with at least one atom or group selected from Group A, represents a C6 to C14 arylsulfonyl group wherein at least one of the C6 to C14 arylsulfonyl groups The hydrogen atom may be optionally substituted with an atom or group selected from Group A, and when two or more atoms or groups are substituted, the atoms or groups may be different from each other.

Examples of the C6 to C14 arylsulfonyl group which may be optionally substituted include a phenylsulfonyl group, a tolylsulfonyl group, a naphthylsulfonyl group, a nitrophenylsulfonyl group, a chlorophenylsulfonyl group, an anisyl group. Sulfonyl, chlorofluorophenylsulfonyl, dimethoxyphenylsulfonyl, pentafluorophenylsulfonyl, trifluoromethylphenylsulfonyl and trifluoromethoxyphenylsulfonyl . Among these, a phenylsulfonyl group and a 4-tolylsulfonyl group are preferred.

The C6 to C14 arylsulfonyl group herein means a monocyclic or polycyclic arylsulfonyl group having 6 to 14 carbon atoms, and the rings may be condensed. Examples of the C6 to C14 arylsulfonyl group include a phenylsulfonyl group, a tolylsulfonyl group, a naphthylsulfonyl group, a biphenylsulfonyl group, an indanyl group, a sulfonyl group, and - Tert-butylphenylsulfonyl. Among these, phenyl Sulfonyl and 4-tolylsulfonyl are desirable.

Herein, at least one hydrogen atom of the benzene ring is optionally substituted with a benzyl group selected from the group or group selected from the group B, and represents a benzyl group in which at least one hydrogen atom of the benzene ring is optionally selected from the group B. An atom or group is substituted, and when two or more atoms or groups are substituted, the atoms or groups may be different from each other. Examples of the optionally substituted benzyl group include a benzyl group, a tolylmethyl group (methylbenzyl group), a chlorophenylmethyl (chlorobenzyl group), an anisylmethyl group (methoxybenzyl group), and a dimethoxy group. Phenylmethyl (dimethoxybenzyl), nitrophenylmethyl (nitrobenzyl), trifluoromethylphenylmethyl (trifluoromethylbenzyl), cyclopropoxyphenylmethyl (2,2-Dichlorocyclopropoxy)phenylmethyl, and trifluoromethoxyphenylmethyl (trifluoromethoxybenzyl). Among these, benzyl, tolylmethyl, chlorophenylmethyl and anisylmethyl are preferred, and benzyl and 4-anisylmethyl are particularly preferred.

The halogenated C1 to C4 alkoxy group as used herein means that at least one hydrogen atom of a linear, branched or cyclic alkoxy group having 1 to 4 carbon atoms is optionally substituted by a halogen atom, and When two or more halogen atoms are substituted, the halogen atoms may be different from each other. Examples of the linear, branched or cyclic alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a cyclopropoxy group, a butoxy group, and Examples of the tertiary butoxy group, optionally halogenated C1 to C4 alkoxy groups include methoxy, 2,2,2-trichloroethoxy, trifluoromethoxy, ethoxy, propoxy, Isopropoxy, 2,2-dichlorocyclopropoxy, butoxy, tert-butoxy, pentafluoroethoxy and 3,3-dichloro-3-fluoropropoxy.

Examples of the chlorinating agent include phosphorus oxychloride, phosphorus trichloride, Phosphorus pentachloride, sulphur sulphur chloride, sulphur sulphur chloride, phosgene and mixtures thereof, and phosphorus oxychloride is preferred.

The secondary amine herein refers to a secondary chain amine and a secondary cyclic amine, while the secondary chain amine includes dimethylamine, diethylamine, diisopropylamine, etc., and the secondary cyclic amine includes pyrrolidine, piperidine, morpholine. And an azole (e.g., imidazole, 1,2,4-triazole) which is unsubstituted on a nitrogen atom. Among these, a secondary cyclic amine is preferred, and piperidine and morpholine are particularly preferred.

Specific examples of the compound [1] include the following compounds: a compound of the formula [1] wherein each of X and Y is a hydrogen atom.

Specific examples of the compound [2] include the following compounds: a compound of the formula [2] wherein each of X and Y is a hydrogen atom.

Specific examples of the compound [3] include the following compounds: a compound of the formula [3] wherein each of X and Y is a hydrogen atom; a compound of the formula [3], wherein Q is a C6 to C24 arylsulfonyl group, at least A hydrogen atom is optionally substituted with an atom or group selected from Group A, or a benzyl group, wherein at least one hydrogen atom of the benzene ring is optionally substituted with a group of atoms or groups selected from Group B; a compound of the formula [3] Wherein Q is a C6 to C24 arylsulfonyl or benzyl group; a compound of the formula [3] wherein Q is a C6 to C14 arylsulfonyl or benzyl group; a compound of the formula [3] wherein Q Is a 4-tolylsulfonyl group, a phenylsulfonyl group or a benzyl group; a compound of the formula [3] wherein Q is a 4-tolylsulfonyl group or a phenylsulfonyl group; a compound of the formula [3], Wherein Q is a 4-tolylsulfonyl group; a compound of the formula [3], wherein Q is a phenylsulfonyl group; a compound of the formula [3], wherein Q is a benzyl group; a compound of the formula [3], Wherein X and Y are each a hydrogen atom, and Q is a C6 to C24 arylsulfonyl group, wherein at least one hydrogen atom is optionally substituted with an atom or group selected from Group A, or a benzyl group, wherein the benzene ring At least one hydrogen atom It is required to be substituted with an atom or a group selected from Group B; wherein the X and Y are each a hydrogen atom, and Q is a C6 to C24 arylsulfonyl or benzyl group; And a compound of the formula [3] wherein X and Y are each a hydrogen atom, and Q is 4- A tolylsulfonyl group, a phenylsulfonyl group or a benzyl group; a compound of the formula [3] wherein each of X and Y is a hydrogen atom, and Q is a 4-tolylsulfonyl group or a phenylsulfonyl group; A compound according to [3], wherein X and Y are each a hydrogen atom, and Q is a phenylsulfonyl group; a compound of the formula [3] wherein X and Y are each a hydrogen atom, and Q is a 4-tolylsulfonate. A compound of the formula [3], wherein X and Y are each a hydrogen atom, and Q is a benzyl group; a compound of the formula [3] wherein X is a fluorine atom, Y is a hydrogen atom, and Q is a phenyl group. A sulfonyl group; a compound of the formula [3], wherein X is a fluorine atom, Y is a hydrogen atom, and Q is a 4-tolylsulfonyl group; a compound of the formula [3], wherein X is a fluorine atom, and Y is a hydrogen atom, and Q is a benzyl group; a compound of the formula [3] wherein X is a fluorine atom and Y is a chlorine atom And Q is a 4-tolylsulfonyl group; a compound of the formula [3] wherein X is a hydrogen atom, Y is a chlorine atom, and Q is a benzyl group; and specific examples of the compound [4] include the following compounds: a compound of 4, wherein Y is a hydrogen atom; a compound of the formula [4], wherein R ¹ is a C1 to C12 alkyl group, wherein at least one hydrogen atom is optionally substituted by a halogen atom, or a C6 to C24 aryl group, wherein At least one hydrogen atom is optionally substituted with an atom or group selected from Group A; wherein R ¹ is a C1 to C12 alkyl group or C6 to C24; a compound of the formula [4], wherein R ¹ is a C1 to C6 alkyl group, wherein at least one hydrogen atom is optionally substituted by a halogen atom, or a C6 to C14 aryl group, wherein at least one hydrogen atom is optionally substituted with an atom or group selected from Group A; a compound according to 4, wherein R ¹ is a C1 to C6 alkyl group or a C6 to C14 aryl group; a compound of the formula [4], wherein R ¹ is a methyl group, a phenyl group or a 4-tolyl group; A compound wherein R ¹ is methyl; a compound of the formula [4], wherein Q is 4-tolylsulfonyl; a compound of the formula [4], wherein R ¹ is methyl and Q is phenylsulfonate.醯基;式[4 a compound wherein R ¹ is a methyl group, and Q is a 4-tolylsulfonyl group; a compound of the formula [4], wherein Y is a hydrogen atom, and Q is a C6 to C24 arylsulfonyl group, wherein at least A hydrogen atom is optionally substituted with an atom or group selected from Group A, or a benzyl group, wherein at least one hydrogen atom of the benzene ring is optionally substituted with an atom or group selected from Group B, and R ¹ is If desired, a halogenated C1 to C6 alkyl group, or a C6 to C24 aryl group, wherein at least one hydrogen atom is optionally substituted with an atom or group of the selected Group A; a compound of the formula [4] wherein Y is a hydrogen atom , Q is a C6 to C24 arylsulfonyl or benzyl group, and R ¹ is a C1 to C6 alkyl group or a C6 to C24 aryl group; a compound of the formula [4] wherein Y is a hydrogen atom and Q is a C6 to C14 group. Arylsulfonyl or benzyl, and R ¹ is C1 to C6 alkyl or C6 to C14 aryl; a compound of the formula [4] wherein Y is a hydrogen atom and Q is 4-tolylsulfonyl or benzyl And R ¹ is a methyl group, a phenyl group or a 4-tolyl group; a compound of the formula [4], wherein Y is a hydrogen atom, and Q is a C6 to C24 arylsulfonyl group, wherein at least one hydrogen atom is optionally Substituted by an atom or group selected from group A And R ¹ is an optionally halogenated C1 to C6 alkyl group; a compound of the formula [4], wherein Y is a hydrogen atom, Q is a C6 to C24 aryl sulfonic acyl group, and R ¹ is C1 to C6 alkyl; A compound of the formula [4], wherein Y is a hydrogen atom, Q is a C6 to C14 arylsulfonyl group, and R ¹ is a C1 to C6 alkyl group; a compound of the formula [4], wherein Y is a hydrogen atom, Q Is a 4-tolylsulfonyl group, and R ¹ is a methyl group; a compound of the formula [4], wherein Y is a hydrogen atom, and Q is a benzyl group, wherein at least one hydrogen atom on the benzene ring is optionally selected from the group consisting of Substituted by a group or group of groups B, and R ¹ is a C6 to C24 aryl group, wherein at least one hydrogen atom is optionally substituted with an atom or group selected from group A; a compound of formula [4], wherein Y Is a hydrogen atom, Q is a benzyl group, and R ¹ is a C6 to C24 aryl group; a compound of the formula [4] wherein Y is a hydrogen atom, Q is a benzyl group, and R ¹ is a C6 to C14 aryl group; a compound according to 4, wherein Y is a hydrogen atom, Q is a benzyl group, and R ¹ is a phenyl group or a 4-tolyl group; a compound compound of the formula [4], wherein R ¹ is a phenyl group; compound, wherein R ¹ is phenyl, 4-methylphenyl and Q is sulfo acyl group; the formula [4] Thereof, wherein R ¹ is phenyl or 4-methylphenyl group, and Q is benzyl; the formula [4] with a compound, wherein R ¹ is phenyl, and Q is benzyl; the formula [4] the compound, Wherein Y is a hydrogen atom and Q is a benzyl group; a compound of the formula [4] wherein Y is a hydrogen atom, Q is a 4-tolylsulfonyl group, and R ¹ is a phenyl group; a compound of the formula [4] Wherein R ¹ is a methyl group, Y is a chlorine atom, and Q is a 4-tolylsulfonyl group; a compound of the formula [4] wherein R ¹ is a methyl group, Y is a hydrogen atom, and Q is a benzyl group. A compound of the formula [4], wherein R ¹ is a methyl group, Y is a hydrogen atom, and Q is a phenylsulfonyl group; a compound of the formula [4], wherein R ¹ is a methyl group, and Y is a hydrogen atom, And Q is a 4-tolylsulfonyl group; a compound of the formula [4], wherein R ¹ is a phenyl group, Y is a chlorine atom, and Q is a 4-tolylsulfonyl group; a compound of the formula [4], wherein R ¹ is phenyl, Y is a hydrogen atom, and Q is a benzyl group; a compound of the formula [4] wherein R ¹ is a phenyl group, Y is a hydrogen atom, and Q is a phenylsulfonyl group; ] compounds, wherein R ¹ is phenyl, Y is a hydrogen atom, and Q is 4-toluene sulfonic acyl group; the compound [5] specific examples include Compound: compound of formula [5], wherein X is a hydrogen atom; Next, the steps of the method of the present invention. The code numbers in the various formulas have the same meanings as described above.

(Manufacturing method 1)

The procedure for producing the compound [3] will be explained below.

The compound [3] can be produced by reacting the compound [4] with the compound [5].

The code name has the same meaning as above.

The reaction is usually carried out in a solvent. Examples of the solvent include hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran, cyclopentyl methyl ether, and ethylene glycol dimethyl ether, and mixtures thereof.

The reaction temperature is usually in the range of -20 to 30 ° C, and more desirably in the range of 0 to 5 ° C. The reaction time is usually in the range of 1 to 100 hours.

The amount of the compound [5] used for the reaction is usually from 1 to 10 moles, preferably from 1 to 1.2 moles, based on 1 mole of the compound [4].

After completion of the reaction, for example, the reaction mixture is mixed with hydrochloric acid or sulfuric acid, and then the precipitate is collected by filtration or extracted with an organic solvent, and the obtained organic layer is operated, for example, by drying and concentration, and the compound [3] can be isolated. The isolated compound [3] can be further purified by column chromatography, recrystallization, or the like.

(Manufacturing method 2)

The procedure for producing the compound [2] from the compound [3] will be described below.

Compound [2] can be produced by deprotection of compound [3].

The code name has the same meaning as above.

Compound [2] may be the compound [3] is deprotected according to known methods to manufacture, e.g., Greene et al., Protective Groups in Organic Chemistry, 4 th .WILEY INSTERSCIENCE, and Journal of Heterocyclic Chemistryi.2003,203, etc. Said method.

(Manufacturing method 3)

The procedure for producing the compound [1] from the compound [2] will be described below.

The compound [1] can be produced by reacting the compound [2] with a chlorinating agent.

The code name has the same meaning as above.

The reaction can be carried out in accordance with the method described in US 7,569,518.

(Manufacturing method 4)

The procedure for producing the compound [1] from the compound [3] will be described below.

The compound [1] can be produced by mixing the compound [3] with phosphorus oxychloride and heating the mixture.

The code name has the same meaning as above.

The reaction is usually carried out in a solvent. Examples of the solvent include hydrocarbons such as toluene and xylene, and halogenated hydrocarbons such as chloroform and chlorobenzene, and phosphorus oxychloride can also be used as a solvent.

The reaction temperature is usually in the range of 60 to 180 ° C, and the reaction time is usually in the range of 1 to 100 hours.

The amount of phosphorus oxychloride used is usually from 1 to 20 moles, preferably from 1 to 5 moles, based on 1 mole of the compound [3].

After the reaction is completed, for example, the reaction mixture is mixed with water or an aqueous alkaline solution such as an aqueous sodium hydroxide solution, and then the precipitate is collected by filtration or extracted with an organic solvent, and the obtained organic layer is operated, for example, by drying and concentration, and can be used as a single From the compound [1]. The obtained compound [1] can be further purified by column chromatography, recrystallization or the like.

(Manufacturing method 5)

The procedure for producing the compound [3A] from the compound [4A] will be described below.

The compound [3A] can be produced by reacting the compound [4A] with the compound [5].

The code name has the same meaning as above.

The compound [3A] can be produced according to the production method 1 by substituting the compound [4A] for the compound [4].

(Manufacturing method 6)

The procedure for producing the compound [1] from the compound [3A] will be described below.

The compound [1] can be produced by mixing the compound [3A] with a secondary amine to deprotect the Q ¹ and then adding a chlorinating agent to the resulting mixture.

The code name has the same meaning as above.

The reaction is usually carried out in a solvent. Examples of the solvent include hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as chlorobenzene, ethers such as tetrahydrofuran, cyclopentyl methyl ether and ethylene glycol dimethyl ether, and mixtures thereof.

The reaction temperature is usually in the range of 20 to 150 ° C, and the reaction time is usually in the range of 1 to 100 hours.

Examples of secondary amines include chain amines such as dimethylamine, diethyl Amines and diisopropylamines, and cyclic amines such as pyrrolidine, piperidine, morpholine, imidazole and 1,2,4-triazole, among which cycloamine is preferred, and piperidine and morpholine are particularly desirable. .

The amount of the secondary amine used is usually 1 to 2 moles based on 1 mole of the compound [3A], and is desirably a ratio of 1 to 1.2 moles.

Examples of the chlorinating agent include phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosgene, and mixtures thereof, and phosphorus oxychloride is preferred.

The chlorinating agent is used in an amount of usually 5 to 10 moles, preferably 1 to 3 moles, and more desirably 1 to 1.1 moles, based on 1 mole of the compound [3A].

After the reaction is completed, for example, the reaction mixture is mixed with water or an aqueous alkaline solution such as an aqueous solution of sodium hydroxide, and then the precipitate is collected by filtration or extracted with an organic solvent, and the obtained organic layer is subjected to, for example, drying and concentration. Isolation of the compound [1]. The compound [1] obtained by isolation may be further purified by column chromatography, recrystallization, or the like.

(Refer to Manufacturing Method 1)

Next, the production steps of the compound [4] will be described below.

The compound [4] can be produced by protecting the nitrogen atom of the compound represented by the formula [6].

Wherein Y and R ¹ have the same meaning as described above (hereinafter referred to as compound [6])

The code name has the same meaning as above.

When Q of the compound to be produced is Q ¹ of the compound [4] (that is, the compound [4A]), the compound [4A] can be produced by reacting a compound represented by the formula [7] with a compound represented by the formula [6].

Q ¹ -C1 [7]

The code number therein has the same meaning as described above.

(hereinafter referred to as compound [7])

Examples of the compound [7] include methylsulfonium chloride, ethylsulfonium chloride, propylsulfonium chloride, tertiary butylsulfonium chloride, pentylsulfonium chloride, hexylsulfonium chloride, heptylsulfonium chloride, Octylsulfonium chloride, mercaptosulfonium chloride, mercaptosulfonium chloride, eleven alkylsulfonium chloride, dodecylsulfonium chloride, isoamylsulfonium chloride, tertiary hexylsulfonyl chloride, cyclopropylsulfonate醯Chlorine, cyclohexylsulfonium chloride, cyclohexylmethylsulfonium chloride, sulfhydrylsulfonium chloride, adamantylsulfonium chloride, p-methylphenylsulfonium chloride, phenylsulfonyl chloride, naphthylsulfonate Chlorine, 2,4,6-trimethylsulfonyl chloride, biphenylsulfonyl chloride, mercaptosulfonyl chloride, mercaptosulfonyl chloride, triphenylsulfonium chloride, binaphthylsulfonate Neodymium chloride, tetraphenylsulfonium chloride, 3',5'-diphenylbiphenylsulfonium chloride, nitrophenylsulfonium chloride, chlorophenylsulfonium chloride, anisylsulfonium chloride, chlorofluorobenzene Sulfonyl chloride, dimethoxybenzene Alkyl sulfonium chloride and pentafluorophenyl sulfonium chloride.

The reaction is usually carried out in a solvent. Examples of the solvent include ethers such as tetrahydrofuran, cyclopentyl methyl ether and ethylene glycol dimethyl ether, hydrocarbons such as toluene, and xylene, halogenated hydrocarbons such as chlorobenzene, and aprotic polar solvents such as dimethylformamidine. Amine, N-methylpyrrolidin-2-one, ethyl acetate, butyl acetate, acetonitrile, acetone and 2-butanone, and mixtures thereof.

The reaction is usually carried out in the presence of a base, for example, an inorganic base. Examples of the base include alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as potassium carbonate and sodium carbonate, and organic salts such as triethylamine, pyridine, dimethyl Aniline and N,N-dimethylaminopyridine (DMAP) and mixtures of these.

The reaction temperature is usually in the range of from -20 to 100 ° C, and the reaction time is usually in the range of from 1 to 100 hours.

The compound [7] is used in an amount of usually 1 to 2 moles based on 1 mole of the compound [6], and is preferably a ratio of 1 to 1.2 moles by cost.

The amount of base used is usually from 1 to 100 moles, and desirably from 1 to 1.2 moles, based on 1 mole of compound [6].

After completion of the reaction, for example, the reaction mixture is mixed with water or mixed with hydrochloric acid or sulfuric acid and neutralized, and then extracted with an organic solvent, and the resulting organic layer is subjected to, for example, drying and concentration, and the compound [4] can be isolated. The obtained compound [4] can be further purified by column chromatography, recrystallization, or the like.

Q in the compound [4] is a benzyl group, and the benzene ring thereof A hydroxy group such as benzyl chloride, methylbenzyl chloride, methoxybenzyl chloride or dimethoxybenzyl may be added to the compound which is substituted with an atom or a group selected from the group B. Chlorine or nitrobenzyl chloride, or benzyl bromide such as benzyl bromide, methylbenzyl bromide, methoxybenzyl bromide, dimethoxybenzyl bromide or nitrobenzyl bromide, reacted with compound [6] And manufacturing.

The reaction is usually carried out in a solvent. Examples of the solvent include hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as chlorobenzene and chloroform, ethers such as tetrahydrofuran, cyclopentyl methyl ether and ethylene glycol dimethyl ether, and aprotic polar solvents such as dimethyl. Mercaptoamine, N-methylpyrrolidin-2-one, ethyl acetate, butyl acetate, acetonitrile, acetone and 2-butane-one, alcohols such as methanol, and mixtures thereof.

The reaction is usually carried out in the presence of a base.

Examples of the base include alkali metal hydrides such as sodium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, inorganic salts such as alkali metal carbonates such as potassium carbonate and sodium carbonate, and organic salts such as triethylamine. , pyridine and dimethylaniline.

The reaction temperature is usually in the range of from -20 ° C to the boiling point of the solvent, and the reaction time is usually from 1 to 100 hours.

The amount of benzyl chloride or benzyl bromide used is usually from 1 to 10 moles, and desirably from 1 to 1.2 moles, based on 1 mole of the compound [6].

The amount of base used is usually from 1 to 100 moles, and desirably from 1 to 1.2 moles, based on 1 mole of compound [6].

After the reaction is completed, for example, the reaction mixture and water The mixture is mixed or neutralized with hydrochloric acid or sulfuric acid, and then extracted with an organic solvent, and the obtained organic layer is operated, for example, by drying and concentration, and can be isolated from the compound [6]. The obtained compound [6] can be further purified by column chromatography, recrystallization, or the like.

Compound [6] can be produced according to a known method, for example, the method described in US 2009/156608.

(Refer to Manufacturing Method 2)

Next, the procedure for producing the compound [5] will be described below.

The compound [5] can be produced by a known method, for example, by reacting a compound represented by the formula [8] (hereinafter referred to as the compound [8]) with magnesium (Mg) or isopropylmagnesium chloride (iPrMgCl).

Wherein i-Pr represents an isopropyl group, and Z has the same meaning as described above.

Compound [5] was used in the next step without isolation and purification.

The reaction is usually carried out in a solvent. Examples of the solvent include ethers such as tetrahydrofuran, cyclopentyl methyl ether and ethylene glycol dimethyl ether, hydrocarbons such as toluene and xylene, and mixtures thereof.

The reaction temperature is usually in the range of from -20 to 30 ° C, and desirably from 0 to 5 ° C, and the reaction time is usually in the range of from 1 to 100 hours.

The amount of Mg used is based on 1 mole of compound [8] which is usually 1 to 1.5 moles, and ideally a ratio of 1 to 1.05 moles.

When Mg is used in the reaction, it is desirable to add 1,2-dibromomethane or the like as a reaction initiator, and these amounts are preferably used in a ratio of 0.001 to 0.01 mol based on 1 mol of the compound [8].

When Mg is used in the reaction, the solvent is desirably an ether such as tetrahydrofuran.

The amount of isopropyl magnesium chloride used is usually in the range of 1 to 1.5 moles based on 1 mole of the compound [8], and more desirably in the range of 1 to 1.05 moles.

Example

Hereinafter, the present invention will be described in more detail by way of examples, but the invention is not limited thereto.

The code numbers in this document indicate the following meanings.

Ms represents a methylalkylsulfonyl group.

Ts represents 4-tolylsulfonyl.

Ph represents a phenyl group.

Bn represents a benzyl group.

MTBE represents a tertiary butyl methyl ether.

THF represents tetrahydrofuran.

example 1

Under a nitrogen atmosphere, 0.3 g of Mg and 15 mL of THF were mixed and stirred at 0 °C. Add a total amount of 0.08 g of 1,2-dibromomethane in 0.5 mL of THF and 1.5 mL of 2.0 g of 1-bromo-2,6-difluorobenzene in 10.0 mL of THF (hereinafter referred to as compound) (8-1)). After 5 minutes, another 2.5 mL of the compound (8-1) solution was added. After the mixture was stirred for a while, the amount of the remaining compound (8-1) solution was added dropwise, and the mixture was stirred at 0 ° C for 2 hours. The solution of 2,6-difluorophenylmagnesium bromide (hereinafter referred to as compound (5-1)) prepared as described above was transferred to a dropping funnel maintained at 0 °C.

In a separate reaction vessel, 4.0 g of 4-methylalkylsulfonyl-6-methyl-5-phenyl-2-{4-methylsulfonyl)-2H-oxime 3-ketone (hereinafter referred to as compound (4-1)) and 10.0 mL of THF were mixed and stirred at 0 °C. The compound (5-1) solution was added dropwise thereto over about 15 minutes, and the mixture was further stirred at 0 ° C for 6 hours. The reaction mixture was allowed to warm to room temperature and 10% hydrochloric acid and hexane were added. The mixture was stirred vigorously and filtered. The material on the filter paper was washed successively with water, MTBE and hexane, and the material on the filter paper was dried under reduced pressure at 50 ° C to obtain 4.0 g (yield 92%) of 4-(2,6-di). Fluorophenyl)-6-methyl-5-phenyl-2-(4-methylsulfonyl)-2H-indole A white solid of -3-ketone (hereinafter referred to as compound (3-1)).

Compound (3-1)

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 8.12 (2H, d, J = 8.3 Hz), 7.36 (2H, d, J = 8.1 Hz), 7.29-7.24 (3H, m), 7.19- 7.11 (1H, m), 7.07-7.03 (2H, m), 6.70 (2H, dd, J = 8.3, 7.3 Hz), 2.45 (3H, s), 2.23 (3H, s).

Example 2

Experiment 1: 105 mg of the compound (8-1) was stirred in a 1.0 mL THF solution under a nitrogen atmosphere at 0 ° C, and 0.3 mL of a 2M isopropylmagnesium chloride-THF solution was added thereto, and the mixture was stirred at the same temperature for 1 hour. Instead, a solution of 2,6-difluorophenylmagnesium chloride (hereinafter referred to as the compound (5-2)) was prepared, and then the solution was kept at 0 °C.

Experiment 2: A solution of 105 mg of the compound (8-1) in 1.0 mL of THF was stirred under a nitrogen atmosphere at 0 ° C, and 0.3 mL of a 2M solution of isopropylmagnesium chloride-THF was added, and the mixture was stirred at the same temperature for one hour. A solution of the compound (5-2) was prepared, and then the solution was kept at 0 °C.

In a separate reaction vessel, 200 mg of 6-methyl-5-phenyl-4-phenylsulfonyl-2-(4-methylsulfonyl)-2H-indole A mixture of 3-ketone (hereinafter referred to as compound (4-3)) and 1.0 mL of THF was stirred under a nitrogen atmosphere at 0 ° C, and the total amount of the compound (5-2) solution prepared in Experiment 1 was added. The mixture was stirred at the same temperature for 1.5 hours, and the total amount of the solution of the compound (5-2) prepared in Experiment 2 was added, and the mixture was further stirred for 1 hour. Hydrochloric acid, MTBE and ethyl acetate were added to the mixture, and the separated organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the obtained compound (3-1) was obtained by LC-IS (Internal Standard).

Example 3

Experiment 1: 108 mg of the compound (8-1) was stirred in a 1.0 mL THF solution at 0 ° C under nitrogen, 0.3 mL of a 2M isopropylmagnesium chloride-THF solution was added, and the mixture was stirred at the same temperature for 1 hour. A solution of the compound (5-2) was prepared, and the solution was kept at 0 °C.

Experiment 2: 108 mg of the compound (8-1) was stirred in a 1.0 mL THF solution under a nitrogen atmosphere at 0 ° C, and 0.3 mL of a 2M solution of isopropylmagnesium chloride-THF was added thereto, and the mixture was stirred at the same temperature for 1 hour. Preparation of compounds (5-2) The solution was then kept at 0 °C.

In a separate reaction vessel, 200 mg of 2-benzyl-6-methyl-5-phenyl-4-phenylsulfonyl-2H-indole A mixture of 3-ketone (hereinafter referred to as compound (4-4)) and 1.0 mL of THF was stirred under a nitrogen atmosphere at 0 ° C, and the total amount of the compound (5-2) solution prepared in Experiment 1 was added. The mixture was stirred at the same temperature for 1.5 hours, then the total amount of the solution of the compound (5-2) prepared in Experiment 2 was added, and the mixture was further stirred for 1 hour. Hydrochloric acid and ethyl acetate were added to the mixture, and the separated aqueous layer was extracted with ethyl acetate, and then the organic layer was mixed and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate to give 2-benzyl-4-(2,6-difluorophenyl 1-6-methyl-5-phenyl-2H-indole The yield of 3-ketone (hereinafter referred to as compound (3-2)) was 96% by LC-IS.

Compound (3-2)

¹ H-NMR (COCl ₃ , TMS) δ (ppm): 7.55 (2H, d, J = 6.6 Hz), 7.39-7.31 (3H, m}, 7.26-7.25 (3H, m), 7.16-7.14 (1H , m), 7.08-7.07 (2H, m), 6.73 (2H, dd, J = 8.3, 7.3 Hz), 5.39 (2H, s), 2.12 (3H, 5).

Example 4

0.3 g of the compound (8-1) was stirred in a 4.0 mL THF solution under a nitrogen atmosphere at 0 ° C, and 0.8 mL of a 2.0 M isopropylmagnesium chloride-THF solution was added, and then the mixture was stirred at the same temperature for 1 hour. . Then, 0.5 g of 2-benzyl-4-methylalkylsulfonyl-6-methyl-5-phenyl-2H-indole was added. 3-ketone (hereinafter referred to as compound (4-2), the mixture was stirred for further 16 hours. 1N hydrochloric acid was added to the mixture, the mixture was brought back to room temperature, 20 mL of 1N hydrochloric acid and 30 mL of water were added, and the mixture was made up to 60 mL. The ethyl acetate was extracted twice. The extract was combined and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (solvent solvent: hexane-ethyl acetate) 2) (yield 60%).

Example 5

A mixture of 235 mg of the compound (3-1), 56 mg of morpholine and 856 mg of toluene was heated and stirred at 50 ° C for 2.5 hours, at 80 ° C for 4 hours, and at 100 ° C for 2.5 hours. The reaction mixture was cooled to room temperature, then 1.0 mL of hexane was added, and the mixture was filtered. The residue was washed with hexane and dried under reduced pressure to give 227 g of white solid. The yield of the compound (2-1) was 74% based on ¹ H-NMR.

Example 6

136 mg of 4-(2,6-difluorophenyl)-6-methyl-5-phenyl-2H-indole A mixture of 3-ketone (hereinafter referred to as compound (2-1)) and 865 mg of toluene was heated and stirred under a nitrogen atmosphere at 100 ° C, and 0.1 mL of phosphorus oxychloride was added. The mixture was heated and stirred for a further 4.5 hours, then cooled to room temperature and a 10% aqueous solution of sodium hydroxide and ethyl acetate were added to the mixture. The separated aqueous layer was extracted twice with ethyl acetate. The organic layers were combined and treated by LC-IS quantitative method to give a compound (1-1) yield of 85%.

Example 7

A mixture of 2.0 g of the compound (3-1), 399 mg of piperidine and 10.0 g of toluene was heated under a nitrogen atmosphere at 100 ° C for 5 hours, and then cooled to room temperature. 0.4 mL of phosphorus oxychloride was added thereto, and the mixture was heated and stirred at 100 ° C for 9 hours. 0.1 mL of phosphorus oxychloride was added to the mixture at 100 ° C, and the mixture was heated and stirred at 100 ° C for 4 hours, cooled to room temperature, and 9.4 g of a 10% aqueous sodium hydroxide solution was added to separate the mixture. The aqueous layer was extracted with toluene and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and 3-chloro-4-(2,6-difluorophenyl)-6-methyl-5-phenylindole The yield (hereinafter referred to as the compound (1-1)) by the LC-IS quantitative method was 80%. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced The crude product was recrystallized from methanol-MTBE to give 0.7 g of object. Yield: 51%. The filtrate was again concentrated under reduced pressure to give 1.6 g of residue. (Yield 29%, LC-IS quantitative method)

Example 8

A mixture of 202 mg of the compound (3-1), 41 mg of morpholine and 1.0 g of toluene was heated and stirred under a nitrogen atmosphere at 100 ° C for 8 hours, and then 0.2 mL of a 3% morpholine/toluene solution was added, and the mixture was added. It was further heated and stirred at 100 ° C for 4.5 hours. The mixture was cooled to room temperature and 0.05 mL of phosphorus oxychloride was added. The mixture was further heated and stirred at 100 ° C for 7 hours and then cooled to room temperature. Acetonitrile was added to the reaction mixture, and the reaction mixture was then subjected to LC-IS quantification. The yield of the compound (1-1) is 80%.

Reference example 1

Under a nitrogen atmosphere, 16 g of 55% sodium hydride and 870 g of THF were mixed and stirred under a nitrogen atmosphere. The mixture was cooled to 0 ° C and 87 g of 4-methylalkylsulfonyl-6-methyl-5-phenyl-2H-indole was added. 3-ketone (hereinafter referred to as compound (6-1)), followed by addition of 73 g of tosyl chloride, and the mixture was stirred at the same temperature for 2 hours. 88 g of 1N hydrochloric acid was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The mixture was separated by adding 2 kg of water and 7 kg of ethyl acetate to the residue, and the organic layer was washed with 1 kg of saturated brine. The organic layer was concentrated under reduced pressure, 412 g of ethanol was added thereto, the mixture was stirred and then filtered, and then the material on the filter paper was washed with 412 g of ethanol. The obtained residue was dried under reduced pressure to give 131 g of Compound (4-1) (yield: 95%).

Compound (4-1)

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 8.11 (2H, d, J = 7.9 Hz), 7.47-7.45 (3H, m), 7.40 (2H, d, J = 8.0 Hz), 7.16- 7.14 (2H, m), 3.28 (3H, s), 2.48 (3H, s), 2.09 (3H, s).

Reference example 2

Under a nitrogen atmosphere, 18 g of 55% sodium hydride and 950 g of DMF (N,N-dimethylformamide) were mixed and stirred. The mixture was cooled to 0 ° C, and 97 g of the compound (6-1) was slowly added in small portions, followed by 72 g of benzyl bromide, and the mixture was stirred for 2 hours. 73 g of 1N hydrochloric acid was added to the reaction mixture, and 1.7 kg of ethyl acetate and 1.0 kg of water were further added to separate the mixture. The aqueous layer was extracted twice with 1 L of ethyl acetate, and the organic layer was combined, washed with 1 L of saturated brine, dried over anhydrous magnesium sulfate and evaporated. 524 g of ethanol and 53 g of chloroform were added to the concentrated residue, and the mixture was heated to 80 ° C, and then cooled to room temperature. Will sink The precipitated solid was filtered, and the substance on the filter paper was washed twice with 128 g of ethanol, and then the material on the filter paper was dried under reduced pressure to give 112 g of the compound (4-2) (yield: 86%).

Compound (4-2)

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 7.53 (2H, d, J = 7.1 Hz), 7.46-7.44 (3H, m), 7.40-7.34 (3H, m), 7.17-7.14 (2H , m}, 5.37 (2H, s), 3.33 (3H, s), 2.02 (3H, s).

Reference example 3

2.0 g of 6-methyl-5-phenyl-4-phenylsulfonyl-2H-indole A mixture of 3-ketone (hereinafter referred to as compound (6-2)), 1.4 g of p-toluenesulfonyl chloride, 1.1 g of potassium carbonate and 10 g of acetonitrile was heated and stirred at 80 ° C for 4 hours under a nitrogen atmosphere. Cool to room temperature and add water and MTBE to the mixture. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 2.6 g of Compound (4-3). Yield: 89%

Compound (4-3)

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 8.03 (2H, d, J = 7.8 Hz), 7.89 (2H, d, J = 8.1 Hz), 7.59 (1H, t, J = 7.1 Hz) , 7.53-7.49 (3H, m), 7.46 (2H, t, J = 7.6 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.20-7.16 (2H, m), 2.46 (3H, 5), 2.04 (3H, s).

Reference example 4

A mixture of 2.0 g of the compound (6-2), 1.0 g of potassium carbonate, 10 g of methanol and 1.4 g of benzyl bromide was stirred at room temperature for 4.5 hours, and then the mixture was separated by adding MTBE, water and ethyl acetate. Floor. The separated aqueous layer was extracted with ethyl acetate. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate The crude product was treated by silica gel column chromatography (washing solvent: hexane-MTBE) to give 1.5 g of compound (4-4) (yield: 43%).

Compound (4-4)

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 8.00-7.97 (2H, m), 7.60 (1H, t, J = 7.3 Hz), 7.52-7.47 (5H, m), 7.41-7.37 (2H , m), 7.32 - 7.27 (3H, m), 7.22 (2H, dd, J = 7.8, 1.5 Hz), 5.25 (2H, s), 1.97 (3H, s).

Reference example 5

In 190 mL of ethanol, 30.0 g of 2-methanesulfonylacetylhydrazide and 32.1 g of 1-phenylpropane-1,2-dione, 23.7 g of a mixture at room temperature in nitrogen Acetic acid is added under the environment. The mixture was stirred at room temperature for 6 hours and then the precipitated solid was collected by filtration. The filtered residue was washed with ethanol to obtain 50.5 g (yield 90%) of 2- Methylalkylsulfonyl acetic acid 1-methyl-2-oxo-2-phenylethylidene oxime (hereinafter referred to as compound (7-1)).

Compound (7-1)

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.23 (3H, s), 3.11 (3H, s), 4.35 (2H, s), 7.46-7.50 (2H, m), 7.56-7.58 (1H , m), 7.94-7.61 (2H, m), 9.23 (1H, m).

Reference example 6

In a mixture of 4.6 mL of toluene and 564 mg of compound (7-1), 85 mg of piperidine was added under a nitrogen atmosphere at room temperature. The mixture was stirred at 110 ° C for 12 hours and then cooled. Dilute hydrochloric acid was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated. The obtained residue was subjected to silica gel column chromatography (washing solvent: hexane-ethyl acetate) to give 481 mg of Compound (6-1) (yield: 91%).

Compound (6-1)

¹ H-NMR (CDCl ₃ , TMS) δ (ppm): 2.04 (3H, s), 3.36 (3H, s), 7.18-7.21 (2H, m), 7.46-7.52 (3H, m), 11.61 (1H) , br).

Reference example 7

Experiment 1: A mixture of 321 mg of hydrazine 2-phenylsulfonylacetate, 206 mg of 1-phenylpropane-1,2-dione, 186 mg of acetic acid and 1.0 g of methanol was stirred at room temperature for 6 hours.

Experiment 2: A mixture of 322 mg of hydrazine 2-phenylsulfonylacetate, 201 mg of 1-phenylpropane-1,2-dione, 11 mg of acetic acid and 1.0 g of methanol was stirred at room temperature for 6 hours.

The reaction mixtures of Experiment 1 and Experiment 2 were combined, and acetic acid was removed by azeotropy with toluene (addition of toluene and concentration of the mixture under reduced pressure), and then the mixture was concentrated under reduced pressure to give 0.95 g ( LC-purity 88%) 2-phenylsulfonyl acetic acid 1-methyl-2-oxo-2-phenylethylidene hydride (hereinafter referred to as compound (7-2)). Yield: 89% contains LC purity content.

Compound (7-2)

¹ H-NMR (CDCl ₃ , TMS) δ: 8.95 (1H, s), 7.98 (2H, d, J = 7.6 Hz), 7.82 (2H, d, J = 7.8 Hz), 7.68-7.60 (2H, m }, 7.51 (4H, td, J = 7.5, 3.7 Hz), 4.48 (2H, s), 2.14 (3H, s).

Reference Example 8

Mixing 10g of compound (7-2), 2.7g of piperidine and 31g of toluene The mixture was stirred at 90 ° C for 5 hours. The mixture was cooled to 40 ° C, and 20 mL of water, 20 mL of a 10% aqueous sodium hydroxide solution and 20 mL of toluene were added to separate the mixture. The organic layer was extracted with 20 mL of a 10% aqueous sodium hydroxide solution, and the aqueous layers were combined, and then concentrated hydrochloric acid was added with stirring. The precipitated solid was collected by filtration, and the residue was washed sequentially with water and hexane, and dried under reduced pressure to give 9.35 g of Compound (6-2). Yield: 98%

Compound (6-2)

¹ H-NMR (COCl ₃ , TMS) δ: 10.62 (1H, brs), 8.01-7.98 (2H, m), 7.61 (1H, t, J = 7.5 Hz), 7.55-7.48 (5H, m), 7.24 (2H, dd, J = 7.8, 1.8 Hz), 1.99 (3H, s).

Reference Example 9

A solution of the compound (1-1) (15 g) in toluene (35 g) was added to water (48 g) and heated to 90 ° C to remove toluene with water and toluene as an azeotrope. After completely removing toluene, the slurry was filtered and the residue was washed with water and dried under reduced pressure at 40 °C. PXRD analysis of the precipitated solid showed phase purity type 1.

Reference example 10

A solution of the compound (1-1) (15 g) in xylene (45 g) was heated to 100 ° C to form a solution, and n-heptane (30 g) was gradually added at 100 ° C. The solution was cooled to 5 ° C and stirred for 1 hour. The slurry was filtered and washed with n-heptane in a solution of xylene (50 wt%). The precipitate was dried under reduced pressure at 40 °C. PXRD analysis of the precipitated solid showed it to be of phase purity type 1.

Reference example 11

Compound (1-1) was combined with 5 times by weight of methanol and mixed at 63 ° C for 0.3 hours to form a solution. The solution was cooled to 10 ° C and stirred for 1.5 hours. The slurry was filtered and washed with methanol. The precipitate was dried at 50 °C. DSC/TGA and PXRD analysis of the precipitated solid showed a phase purity type of 1. Fig. 1 and Fig. 2 are diagrams showing physical property data of the type 1. The peak list of the PXRD pattern of the type 1 is shown below.

Reference example 12

Compound (1-1) (76.2 mg) was combined with 2 mL of methanol in a 12 mL vial and mixed at 25 ° C for 0.5 hour to form a solution. Pass the solution through 0.2μm The PTFE filter is in a clean 12 mL vial. The vial was placed on a 50 ° C metal block without being capped, and the solvent was allowed to evaporate for 2 days. DSC/TGA and PXRD analysis of the precipitated solid showed phase purity type 2. Fig. 3 and Fig. 4 are diagrams showing the physical property data of the type 2. The lower part indicates the peak list of the PXRD pattern of the type 2.

Reference example 13

Compound (1-1) (260.6 mg) was combined with 8 mL of methanol in a 12 mL vial and mixed at 25 ° C for 0.5 hour to form a solution. The solution was filtered through a 0.2 μm PTFE filter. The solution (about 1 mL) was allowed to evaporate for 3 days in a 12 mL vial loosely capped on a 50 ° C metal block. The DSC and PXRD analyses of the precipitated solids showed a novel, expressed as Form 3. Fig. 5 and Fig. 6 are graphs showing the physical property data of the type 3. The peak list of the PXRD pattern of the type 3 is shown below.

In the seventh embodiment, the solid type 1 to type 3 are different PXRD patterns.

Instrument method:

Powder X-ray diffraction pattern (PXRD). PXRD diffraction pattern using PANalytlcal X'Pert Pro diffraction instrument using Ni- filtered Cu Kα (45kV / 40mA) radiation and step magnitude and 0.02 ° 2θ ^{X'celerator TM RTMS (Real Time Multi-} Step) detector .

The incident light side is configured with a fixed release slit (0.25°), a 0.04 rad Soller slit, an anti-scatter slit (0.25°), and a 10mm beam mask.

Diffraction side configuration: fixed release slit (0.25°) and 0.04 Redsole slit. The sample plane is fixed on a 0 background wafer.

Differential Scanning Calorimeter (DSC). DSC is equipped with at 40mL / min N ₂ purged autosampler and a refrigerated cooling system TA Instruments Q100 differential scanning calorimeter. A DSC thermogram was obtained at 15 ° C/min using a crimped Al disk.

Thermogravimetric Analysis (TGA): The TGA thermogram was obtained by purging with a Pt or Al disk at 40 mL/min N ₂ using a TA Instruments Q500 thermogravimetric analyzer.

Industrial application possibilities

嗒 represented by the formula [1] used as an active ingredient of a plant disease control agent The compounds can be made according to the methods described in the present invention.

Claims (6)

A method for producing a compound represented by the formula [1], which comprises the step of reacting a compound represented by the formula [4] with a compound represented by the formula [5] to obtain a compound represented by the formula [3]: Wherein Q represents a C1 to C12 alkylsulfonyl group which is optionally halogenated, and optionally a C6 to C24 arylsulfonyl group substituted with at least one atom or group selected from Group A, or a benzene ring thereof At least one hydrogen atom is optionally substituted with a benzyl group selected from an atom or group of Group B, X represents a hydrogen atom, a halogen atom or a methyl group, and Y represents a hydrogen atom, a halogen atom or a methyl group; Wherein Q represents a C1 to C12 alkyl group which is halogenated as desired, or a C6 to C24 aryl group which is optionally substituted with at least one atom or group selected from Group A, and Q and Y have the same meanings as described above. , Group A: Groups of halogenated C1 to C4 alkoxy groups, halogen atoms and nitro groups as desired, Group B: C1 to C4 alkyl groups which are halogenated as needed, and C1 to C4 alkoxy groups which are halogenated as needed Group of groups, halogen atoms and nitro groups: Wherein X has the same meaning as defined above, and Z represents a chlorine atom or a bromine atom; and the compound represented by the formula [2] is deprotected from the compound [3]: In the formula, X and Y have the same meanings as defined above; the compound represented by the formula [2] is reacted with a halogenating agent to obtain a compound represented by the formula [1]: Wherein X and Y have the same meanings as described above. A process for producing a compound represented by the formula [1], which comprises the step of reacting a compound represented by the formula [4] with a compound represented by the formula [5] to obtain a compound represented by the formula [3]: Wherein Q represents a C1 to C12 alkylsulfonyl group which is optionally halogenated, optionally substituted with a C6 to C24 arylsulfonyl group selected from at least one atom or group of Group A, or on a benzene ring. At least one hydrogen atom is optionally substituted with a benzyl group selected from an atom or group of Group B, X represents a hydrogen atom, a halogen atom or a methyl group, and Y represents a hydrogen atom, a halogen atom or a methyl group. Wherein R ¹ represents a C1 to C12 alkyl group which is optionally halogenated, or a C6 to C24 aryl group which is optionally substituted with at least one atom or group selected from the group A, and Q and Y have the same meanings as described above. , Group A: Groups of halogenated C1 to C4 alkoxy groups, halogen atoms and nitro groups as desired, Group B: C1 to C4 alkyl groups which are halogenated as needed, and C1 to C4 alkoxy groups which are halogenated as needed Group of groups, halogen atoms and nitro groups, Wherein X has the same meaning as described above, and Z represents a chlorine atom or a bromine atom; and a compound represented by the formula [1] is obtained by mixing the compound [3] with phosphorus oxychloride and heating the mixture: Wherein X and Y have the same meanings as described above. A method for producing a compound represented by the formula [1], which comprises the step of reacting a compound represented by the formula [4A] with a compound represented by the formula [5] to obtain a compound represented by the formula [3A]: Wherein X and Y have the same meanings as defined above, and Q ¹ represents a C1 to C12 alkylsulfonyl group which is optionally halogenated, or a C6 which is optionally substituted with at least one atom or group selected from Group A. To C24 arylsulfonyl, Group A: if desired, a halogenated C1 to C4 alkoxy group, a halogen atom and a nitro group, Wherein R ¹ , Y and Q ¹ have the same meaning as described above, and Wherein X has the same meaning as described above, and Z represents a chlorine atom or a bromine atom; and a compound represented by the formula [3A] is mixed with a secondary amine and then a chlorinating agent is added to the mixture to obtain a compound [1]. A compound represented by the formula [3]: Wherein Q represents a C1 to C12 alkylsulfonyl group which is optionally halogenated, a 6 to C24 arylsulfonyl group which is optionally substituted with at least one atom or group selected from Group A, or at least a benzene ring thereof A hydrogen atom is optionally substituted with a benzyl group selected from an atom or group of Group B, X represents a hydrogen atom, a halogen atom or a methyl group, and Y represents a hydrogen atom, a halogen atom or a methyl group, Group A: halogenated as needed a group of C1 to C4 alkoxy groups, a halogen atom and a nitro group, Group B: a C1 to C4 alkyl group which is halogenated as needed, a halogenated C1 to C4 alkoxy group, a halogen atom and a nitro group, if necessary In groups. A method for producing a compound represented by the formula [3], which comprises reacting a compound represented by the formula [4] with a compound represented by the formula [5]: Wherein Q represents a C1 to C12 alkylsulfonyl group which is optionally halogenated, optionally substituted with a C6 to C24 arylsulfonyl group substituted with at least one atom or group selected from Group A, or a benzene ring thereof At least one hydrogen atom is optionally substituted with a benzyl group selected from an atom or group of Group B, X represents a hydrogen atom, a halogen atom or a methyl group, and Y represents a hydrogen atom, a halogen atom or a methyl group, Group A: as needed a group of halogenated C1 to C4 alkoxy groups, a halogen atom and a nitro group, Group B: a C1 to C4 alkyl group optionally halogenated, a C1 to C4 alkoxy group optionally halogenated, a halogen atom and a nitrate Foundation group, Wherein R ¹ represents a C1 to C12 alkyl group optionally halogenated, or a C6 to C24 aryl group optionally substituted with at least one atom or group selected from the group A, and Q and Y have the same meaning as defined above. significance, Wherein X has the same meaning as described above, and Z represents a chlorine atom or a bromine atom. A compound represented by the formula [4]: Wherein R ¹ represents a C1 to C12 alkyl group which is optionally halogenated, or a C6 to C24 aryl group which is optionally substituted with at least one atom or group selected from the group A, and Q and Y have the same meanings as described above. Group A: a group of a halogenated C1 to C4 alkoxy group, a halogen atom and a nitro group as needed.